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1 2 Analytical Methods RSC Publishing 3 4 5 MINIREVIEW 6 7 8 Cite this: DOI: 9 Caffeic Acid: a review of its potential use for 10 11 medications and cosmetics 12 Received a a a a 13 Accepted C. Magnani, V.L.B. Isaac, M.A. Correa and H.R.N. Salgado 14 DOI: 15 Besides powerful antioxidant activity, increasing collagen production and prevent premature 16 www.rsc.org/ aging, caffeic acid has demonstrated antimicrobial activity and may be promising in the 17 treatment of dermal diseases. The relevance of this study is based on the use of caffeic acid 18 increasingly common in humans. Thus, studies that demonstrate and clarify the functions of 19 this substance are very important. 20
21 Manuscript 22 Introduction 23 24 Characteristics of caffeic acid 25 26 Phenolic compounds occur universally in the plant kingdom 27 and are part of a large and complex group of organic 28 substances. Higher plants synthesize and accumulate a wide 29 variety of phenolic compounds, which confer protection against the attacks of free radicals, which are by products from the 30 1 process of photosynthesis and against tissue injuries. The Fig. 2 Chemical structure of the main cinnamic acids. Cinnamic 31 phenolic compounds can be classified into two groups: group of Accepted acid R1 = R2 = R3 = R4 = H, o coumaric acid: R2 = OH, p 32 simple phenolic compounds and group of polyphenolic 33 compounds which can be observed through the frame shown in coumaric acid: R3 = OH; caffeic acid: R2 = R3 = OH; ferulic 34 Figure 1. 2,3 acid: R2 = OCH3 and R3 = OH. 35 36 Phenolic Compounds Modern consumers increasingly demand products and foods 37 with high quality. Cosmetics may not have as many health 38 implications as pharmaceutical products or food, but they are 39 polyphenols simple chemical products that people use daily and apply on skin, hair, phenolics 4 40 nails and even teeth or mouth. Allied to this, legislation is Methods 41 increasingly strict about quality and safety, which has 5 42 tannins flavonoids phenolic coumarins challenged the industries. For this reason, natural antimicrobial 43 acids compounds, such as polyphenols 6 are being widely used. 44 Caffeic acid (3,4 dihydroxycinnamic) is one of the hydroxy 45 cinnamate and phenylpropanoids metabolites more widely hydroxybenzoic hydroxycinnamic 46 distributed in plant tissues. This polyphenol is present in many acid acid 47 food sources, including coffee drinks, blueberries, apples and 48 Fig. 1 Chemical classification of phenolic compounds. cider 7. Besides food, caffeic acid is present in several 49 medications of popular use, in the majority, based on propolis. 8 50 9,10
Cinnamic acid derivatives, also called phenylpropanoids are Besides acting as a carcinogenic inhibitor , is also known as Analytical 51 nine carbon structures (Figure 2). Caffeic acid (3,4 an antioxidant and antibacterial in vitro, and can contribute to 52 dihydroxycinnamic) is representative of this group. the prevention of atherosclerosis and other cardiovascular 53 11 13 a UNESP Universidade Estadual Paulista, Faculdade de Ciências diseases . 54
55 Farmacêuticas, Departamento de Fármacos e Medicamentos– . 56 Araraquara, SP, Brasil
57 58 59 60 This journal is © The Royal Society of Chemistry 2013 Anal. Methods , 2013, 00 , 1-3 | 1 Analytical Methods Page 2 of 9 ARTICLE Journal Name
1 Antioxidant Activity derived from both normal metabolic processes and essential 2 metabolic processes to the body (endogenous), and they can be 3 4 Antioxidants are compounds that act by inhibiting or derived from exposure to environmental factors (exogenous) 5 reducing the effects triggered by free radicals and oxidizing such as pollution, radiation, pesticides tobacco, among others. compounds. 14 Free radicals can cause beneficial or deleterious effects to 6 28 30 7 The phenolic antioxidants act as free radical scavengers and health. 8 sometimes as metal chelators. They act both in the initiation The importance of reactive oxygen species (ROS) and free 9 step such as on the propagation of the oxidative process. The radicals has attracted increasing attention over the last decade. 10 products are relatively stable due to the resonance of the ROS, which include free radicals such as superoxide anion • • 11 aromatic ring shown by these substances. The phenolic acids radicals (O 2 ), hydroxyl radicals (OH ) and reactive oxygen 12 are characterized by the presence of a benzene ring, a species such as H 2O2 and singlet oxygen (1O 2). These 13 carboxylic acid grouping and one or more hydroxyl or methoxy molecules exacerbate factors of cell damage and aging. 31,32 14 groups of the molecule, which confers antioxidant properties. 15 ROS are continuously produced during normal physiologic 15 The phenylpropanoids act as antioxidants by eliminating events and they can easily initiate the peroxidation of 16 oxygen free radicals 16,17 and chelating pro oxidant metal ions, membrane lipids, leading to the accumulation of lipid 17 especially iron. 18,19 The hydroxyl groups of these molecules peroxides. 33,34 However antioxidants cells have developed 18 confer antioxidant activity, but they are not the only factors in mechanisms to protect themselves from free radical toxicity. 19 determining the potency of their activities. There is a single The agents considered antioxidants include: catalytic enzymes 20 hydroxyl group para substituted in an aromatic ring that is that remove radicals such as superoxide dismutase (SOD); 21 linked to a side chain conjugate in the case of ferulic acid. This proteins which minimizes the availability of pro oxidants, such Manuscript 22 substitution allows the phenoxy radical free electrons to as iron ions and copper ions, for example, transferrins, ferritins, 23 become delocalized over the entire molecule, and therefore metallothionein and haptoglobines; low molecular weight 24 stable. 20 The ortho substitution to the methoxy group, an molecules that have the ability to capture reactive oxygen 25 electron donor, is also a contributing factor to the stability of species through autoxidation such as, for example, those with 26 the phenoxy radical and thus increases the efficiency glutathione and thiol group (SH) or vitamins such as α 27 antioxidant. 21,22 The presence of a second hydroxyl group in the tocopherol, ascorbic acid and β carotene. 35,36 28 ortho position, besides the para position is known to increase When there is an imbalance between pro and antioxidant 29 the antioxidant activity due to a additional resonance system, with a predominance of oxidants, the oxidative stress 30 stabilization and formation of o quinone (Figure 3). 20,21,23 This occurs 37,38 . This stress can be associated with damage to lipids,
31 characteristic can be used to explain the fact that the efficiency proteins and gens and it imply a great variety of human diseases Accepted 32 of antioxidants such as caffeic acid is greater than that of ferulic as well as in the aging process. 39 33 acid. The free radicals also act on the skin tissue, which originate 34 mainly by exogenous actions, such as ultraviolet radiation. 35 Depending on the dose, exposure time, wavelength and area 36 exposed, the ultraviolet radiation can cause skin burns, 37 premature skin aging and even skin cell DNA damage and skin 38 cancer. 40,41 39 Thus, the natural aging of the skin associated with the
40 Methods 41 action of free radicals causes a reduction in skin hydration, 42 pigmentation, fine wrinkles, signals from sagging and increased Fig. 3 Chemical structure of caffeic acid and formation of ortho possibility of the occurrence of neoplasm diseases. Another 43 quinone. 44 change is the reduction of dermal collagen that makes the skin 45 Caffeic acid has been shown to be a α tocopherol protective thinner. These changes are even more evident after menopause, 46 in low density lipoprotein (LDL). 24 Furthermore, their in which there is a rapid decrease in the levels of collagen in 47 combination with other products, such as with chlorogenic and skin and bone, suggesting that estrogen influences the collagen 42 48 caftaric acids showed more potent antioxidant activity in a synthesis in the skin as much bone mass. 49 variety of different systems. 17,25 In order to maintain the skin healthier and younger looking, 50 Natural phenolic antioxidants including caffeic and ferulic thereby mitigating the effects of aging, more strategies have Analytical 51 acids, gained remarkable attention as promising photoprotective been suggested. 30 The use of natural or synthetic antioxidants in 52 agents 26,27 and also have been present in skin care products for foods, cosmetics, beverages and also medicine is one of the 53 its antioxidant activity. However the literature shows little defence mechanisms against free radicals.43 45 54 evidence about the usefulness of hydroxycinnamic acids to Photoaging of the skin is one of the most common 55 protect the skin from photo oxidative damage. dermatological concerns and can become a major health 56 The normal cellular metabolism produces free radicals, concern because it is correlated with an increased risk of skin 57 including reactive species of oxygen and nitrogen, which are cancer. 42 UVA radiation can cause damage clinical, 58 biochemical and histological changes in the skin through 59 60 2 | Anal. Methods , 2013, 00 , 1-3 This journal is © The Royal Society of Chemistry 2012 Page 3 of 9 Analytical Methods Journal Name ARTICLE
1 changes in cells and in extracellular matrix proteins, including independent of the pH of the receptor solution being 3.0 or 2 collagen, responsible for the structural integrity of the skin. 46 7.2. 63 3 4 UVA radiation (315 400 nm) has been shown to elevate As the solar radiation penetrates deeply into the skin, it is 5 matrix metalloproteinase 1 extracellular (collagenase MMP 1), necessary to ensure that topically applied substances are able to most proteolytic enzyme produced by the skin cells, including penetrate through the corneum stratum, the main barrier against 6 47,48 7 keratinocytes and fibroblasts. This activation is related to permeation of foreign substances through the skin and reach the 64 8 oxidative stress, which occurs when there is excessive deepest layers to promote satisfactory photo protection. 9 production of reactive oxygen species and / or depletion of The absorption of a compound in the skin is determined by 49,50 10 antioxidant defences in cells. its physicochemical characteristics, and on the permeation 11 Natural and synthetic antioxidants act as scavenger of free process, the lipophilicity is one of the most important 65 12 radicals and have been shown to promote skin photo protection features. Thus, the high lipophilicity of caffeic and ferulic 13 by repealing the induction of MMP 1 activity mediated by acid may explain the fact to permeate through the stratum 14 UVA radiation and expression of keratinocytes and skin corneum. 66 15 fibroblasts.48,51,52 The ferulic and caffeic acid also demonstrate efficiency to 16 Ultraviolet A (UVA) plays a fundamental topic in the protect phosphatidylcholine peroxidation induced by UV 17 pathogenesis of premature skin aging through cytotoxicity to radiation, which is important since the phosphatidylcholine is a 18 keratinocytes and degradation of collagen, a major component major constituent of the lipid bilayers of cell membranes. 56 19 of the extracellular matrix that provides structural support. 20 Protection against UVA damage mediated through the Antimicrobial Activity 21 antioxidant defence systems has been proposed as a possible Manuscript 22 mechanism by which plant compounds decrease the process of Every day more consumers seek more effective cosmetics, 23 premature aging. 53 which approximate the definition of cosmeceuticals, or actually 24 Furthermore, under stimulation by UVA and UVB sunlight, having some biological effect, particularly in the prevention of 25 keratinocytes from human skin can secrete nitric oxide (a premature aging and diseases such as cancers caused by the 26 radical involved in oxidation reactions). Nitric oxide (NO) action of free radicals in the genes of cells. Therefore, as well 27 appears to have great interest in the formation of erythema and as drugs, these products should also provide security to the 28 skin inflammation.54,55 Both caffeic and ferulic acid act as consumer. Allied to this, legislation is becoming increasingly 29 sequestering radical NO. 56 In light of these observations, the stringent, which has challenged the industries. 4,5 Besides, 30 topical administration of antioxidants found considerable cosmetic companies are required to control the optimal
31 interest, since it represents an effective strategy to protect the preservation of their commercial products, since microbial Accepted 32 skin against oxidative damage mediated by UV.55,57 contamination in cosmetics represents an important risk for 33 The extension of erythema caused by UVB radiation may consumer health. 67 For this reason, natural antimicrobial 34 be monitored through reflectance spectrophotometry, which is compounds are widely used. 6 35 considered one of the most suitable models for the study in vivo Besides its remarkable antioxidant activity, in vitro studies 36 of skin damage after acute exposure to UV. 58,59 Caffeic and have demonstrated antimicrobial properties of propolis against 37 ferulic acids, dissolved in saturated aqueous solutions at pH 7.2, various oral pathogens. Several components of propolis have 38 proved to provide significant photo protection to the skin been analysed in different countries, and caffeic acid, phenethyl 39 against UV induced erythema.56 ester of caffeic acid and flavonoids are the main ingredient
40 68 70 Methods 41 Anti aging products are being increasingly appreciated in responsible for the antibiotic power of this resin. Thus, a recent years and those with active antioxidants in its thorough search of the antimicrobial activity of caffeic acid is 42 60 43 composition are highlighted. promising targeting the treatment of dermal diseases, such as 44 Caffeic acid was an effective antioxidant in different acne. 45 methods for the determination of antioxidant activity in vitro , Some phenylpropanoids, including caffeic acid, p coumaric 46 including total antioxidant activity of the ferric thiocyanate acid and ferulic acid are able to inhibit the growth of bacteria, 47 method, method of inhibition of ABTS•+ and DPPH•, the including E. coli , Staphylococcus aureus , Bacillus cereus , 71 48 superoxide anion radical and metal chelating activity when Listeria monocytogenes and some yeasts. 49 compared with conventional antioxidants such as BHA, BHT, The antimicrobial activity of these substances depends not 50 α tocopherol, a natural antioxidant and Trolox, which is a water only on its structure but also on the environmental conditions. 51 soluble analogue of tocopherol. 61 Caffeic acid has a reduced ability to inhibit Listeria compared Analytical 52 Through the permeation study of caffeic acid, chlorogenic to other hydroxycinnamic acid derivatives due to the presence 53 acid and oraposide, it was found that the caffeic and of a high degree of hydroxylation. 6 Moreover, environmental 54 chlorogenic acids are able to permeate all the skin layers of pig factors, including pH and concentration of sodium chloride are 55 ear, which have a systemic activity, whereas oraposide important because they produce certain physiological changes 56 remained in the upper layer of the skin surface. 62 Permeation in the micro organisms that make them more sensitive to 57 studies with human skin also confirm the ability of caffeic acid phenylpropanoids. 72 58 and ferulic acid permeate into the skin, characteristic 59 60 This journal is © The Royal Society of Chemistry 2012 Anal. Methods , 2013, 00 , 1-3 | 3 Analytical Methods Page 4 of 9 ARTICLE Journal Name
1 Antioxidant and antimicrobial activities of caffeic acid is The p38, a mitogen activated protein kinase (MAPK) 2 pronounced in cosmetic emulsions with acidic pH (3 e 5). responds to stimuli such as heat, shock, cytokines, UV and is 3 89 4 Caffeic Acid showed in this pH, antimicrobial effects against directly involved in cell proliferation and production of NO. 5 various micro organisms studied (E. coli , Pseudomonas Caffeic acid significantly reduces mRNA expression of aeruginosa , Bacillus cereus , Kokuria rhizophila , Interleucin 10 UVB induced in murine and also inhibits the 6 90 7 Staphylococcus aureus , Listeria monocytogenes , Candida activation of p38 MAPK. The caffeic acid also reduces the 73 91 8 albicans ). migratory capacity of malignant keratinocytes. 9 The mechanism of antimicrobial activity of substances is Although many studies demonstrate the antitumoral activity 10 established considering one of the following three: (1) reaction of caffeic acid, others show opposite effects. The 11 with the cell membrane causing increased permeability and loss carcinogenicity of low dietary levels of the antioxidants caffeic 12 of cellular constituents, (2) inactivation enzymatic systems or acid, butylated hydroxyanisole (BHA), sesamol, 4 13 essential enzymes, including those involved in the production methoxyphenol (4 MP) and catechol, were examined alone or 14 process energy and synthesis of structural components, or (3) in combination in a 2 year long term experiment. The results 15 destruction or inactivation functional genetic material.74 75 indicate that even at low dose levels phenolic compounds can 16 exert additive/synergistic effect on carcinogenesis. 92 17 The cytoplasm membrane of bacteria and mitochondrial Furthermore, caffeic acid is also listed under some Hazard Data 18 membrane of yeasts are a permeable barrier to passage of small and in the International Agency for Research on Cancer in the 19 ions such as H +, K +, Na + and Ca ++ , in addition to being Group 2B, as a substance "possibly carcinogenic to humans". 20 responsible for input and output of different compounds. This As there are many controversial results about the protective 21 cell permeability is important for various cell functions such as or carcinogenic potential of caffeic acid, more studies should be Manuscript 22 maintenance of energy in the transduction process, solute conducted to elucidate its therapeutic use. 23 transport, metabolism regulation and pressure control.76 77 24 There is a consensus that aromatic and phenolic compounds, Analytical Methods 25 such as caffeic acid, affect the cytoplasm membrane, alter their 26 structure and function, change the active transport and There is no method for determination and quantification of 27 coagulate cell content. 78 79 caffeic acid in official compendia, such as pharmacopoeias, 28 however most current articles recommends quantification of the 29 Cytotoxicity substance by High Performance Liquid Chromatography 30 (HPLC).
31 Caffeic acid and its derivatives, such as caffeic acid phenyl For determination of rosmarinic and caffeic acids in various Accepted 32 ester, has action against colon and oral cancer, and they are herbs such as rosemary, sage, thyme, mint, lemon balm and 33 inhibitors of cyclooxygenase II (COX 2).80 82 These substances lavender, a HPLC method was developed and validated. The 34 are cytotoxic for tumours but not for normal cells.83 84 separation system consisted of a reversed phase C18 column, a 35 An analysis by flow cytometry showed that the caffeic acid gradient elution system of methanol/water containing 36 and its derivatives caused cellular entrapment of oral squamous phosphoric acid and a photodiode array detector. The method 37 cell carcinoma cells, Meng 1 (OEC M1) in G2/M phase of cell proved to be simple, sensitive, reproducible and fast ideal for 38 division. These differential effects on cancer show that these routine analysis. 93 39 compounds may be useful in cancer chemotherapy oral. 85 For quantitation of receptor solution in a permeation study,
40 Methods 41 Various natural antioxidants were tested, among them the chromatography was performed on a Hypersil ODS column 42 caffeic acid, catechin, epicatechin and quercetin to evaluate the (particle size: 5 m x 25 cm x 4.0 mm). The mobile phase was 43 reduction of the cytotoxicity induced by peroxynitrite in acetonitrile water (18:82) containing 2% acetic acid. The flow 44 chondrosarcoma cells. This observation suggests that diets rich rate was set at 1.0 mL/min. Each sample was filtered before 86 45 in antioxidant compounds are able to limit cell cytotoxicity. injection using a Millex filter and an aliquot (20 mL) was 63 46 A derivative of caffeic acid, the caffeic acid phenyl ester injected into HPLC. Detection was performed at 302 nm. 47 was used and it was observed that it inhibited growth and Marti Mestres and coworkers (2007) conducted a 48 secretion of interleucin 6, and it induced apoptosis in a dose permeation study by applying 50 L of test formulation 2% 49 and time dependent on multiple myeloma cells ARH 77. caffeic acid in propyleneglycol transcutol (1:1) on the skin of 50 Therefore, both the caffeic acid as its derivative deserves the pig's ear and used isotonic saline (NaCl 0.9%) with 1% 51 further study as an effective agent against multiple myeloma. 87 gentamycin pH 7.0 as the receiver solution. This solution was Analytical 52 Treatment of mice with propolis, caffeic acid phenyl ester maintained at 37ºC and under these conditions the skin 53 and caffeic acid itself, significantly reduced the number of temperature is 32ºC, which corresponds to the temperature of 54 tumour nodules in the lungs of animals whose lung nodules the body surface in vivo . The quantification of the receptor 55 were generated by injection of viable tumour cells solution was also carried out by HPLC with UV detection, 56 intravenously. In in vitro studies, the propolis did not affect column C 8 reverse phase (5 m, 250 mm x 3 mm) at 40ºC. 57 tumour cell growth, while the phenyl ester of caffeic acid and The mobile phase was acetonitrile water (18:80) with 2% acetic 58 caffeic acid expressed a strong cytotoxicity to cells. 88 59 60 4 | Anal. Methods , 2013, 00 , 1-3 This journal is © The Royal Society of Chemistry 2012 Page 5 of 9 Analytical Methods Journal Name ARTICLE
1 acid and flow rate of 0.5 mL/min. Detection was at 330 nm and 2 Acknowledgements the retention time was approximately 6.0 min.62 FAPESP, CNPq and PADC FCF UNESP. 3 4 Chromatographic techniques are widely used in the References 5 separation, purification, identification and quantification of
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Manuscript 22 23 24 25 26 27 28 29 30
31 Accepted 32 33 254x190mm (96 x 96 DPI) 34 35 36 37 38 39
40 Methods 41 42 43 44 45 46 47 48 49 50 51 Analytical 52 53 54 55 56 57 58 59 60